Women's Health

The selective neurokinin 3 receptor antagonist fezolinetant was a well tolerated and effective nonhormone therapy for moderate to severe vasomotor symptoms associated with menopause, Graeme L. Fraser, PhD, of Ogeda, a subsidiary of Astellas Pharma, and associates reported in Menopause.

yacobchuk/Getty Images

The investigators conducted a randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study between July 19, 2017, and Sept. 19, 2018, in 287 women who completed the full 12-week trial. The women were aged between 41 and 65 years, were menopausal, and had moderate to severe vasomotor symptoms (VMS) with an incidence of at least 50 episodes per week. The majority of the women were white, 25% were black, 1% were Asian, and 1% were “other.”

The reduction in VMS episodes in patients who received fezolinetant ranged from 1.9 to 3.5 episodes per day at week 4 and from 1.8 to 2.6 per day at week 12. The mean difference from placebo in VMS severity score was –0.4 to –1 at week 4 and was –0.2 to –0.6 at week 12. At least a 50% reduction in VMS frequency at week 12 was achieved by 81%-95% of patients who received fezolinetant, compared with 59% of those who received placebo.

Treatment-emergent adverse events were generally mild to moderate, with the most common events including nausea, diarrhea, fatigue, urinary tract infection, upper respiratory tract infections, sinusitis, headache, and cough. Of the five severe adverse events reported, only two were considered related to treatment – cholelithiasis and drug-induced liver injury. A total of 21 patients discontinued because of adverse events.

“Further evaluation of fezolinetant in larger and longer phase 3 trials of women with VMS associated with menopause is warranted to more fully characterize its efficacy and safety profile,” Dr. Fraser and colleagues concluded.

The study was funded by Astellas Pharma. The investigators reported numerous conflicts of interest with pharmaceutical companies.

[email protected]

SOURCE: Fraser GL et al. Menopause. 2020 Feb 24. doi: 10.1097/GME.0000000000001510.

The selective neurokinin 3 receptor antagonist fezolinetant was a well tolerated and effective nonhormone therapy for moderate to severe vasomotor symptoms associated with menopause, Graeme L. Fraser, PhD, of Ogeda, a subsidiary of Astellas Pharma, and associates reported in Menopause.

yacobchuk/Getty Images

The investigators conducted a randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study between July 19, 2017, and Sept. 19, 2018, in 287 women who completed the full 12-week trial. The women were aged between 41 and 65 years, were menopausal, and had moderate to severe vasomotor symptoms (VMS) with an incidence of at least 50 episodes per week. The majority of the women were white, 25% were black, 1% were Asian, and 1% were “other.”

The reduction in VMS episodes in patients who received fezolinetant ranged from 1.9 to 3.5 episodes per day at week 4 and from 1.8 to 2.6 per day at week 12. The mean difference from placebo in VMS severity score was –0.4 to –1 at week 4 and was –0.2 to –0.6 at week 12. At least a 50% reduction in VMS frequency at week 12 was achieved by 81%-95% of patients who received fezolinetant, compared with 59% of those who received placebo.

Treatment-emergent adverse events were generally mild to moderate, with the most common events including nausea, diarrhea, fatigue, urinary tract infection, upper respiratory tract infections, sinusitis, headache, and cough. Of the five severe adverse events reported, only two were considered related to treatment – cholelithiasis and drug-induced liver injury. A total of 21 patients discontinued because of adverse events.

“Further evaluation of fezolinetant in larger and longer phase 3 trials of women with VMS associated with menopause is warranted to more fully characterize its efficacy and safety profile,” Dr. Fraser and colleagues concluded.

The study was funded by Astellas Pharma. The investigators reported numerous conflicts of interest with pharmaceutical companies.

[email protected]

SOURCE: Fraser GL et al. Menopause. 2020 Feb 24. doi: 10.1097/GME.0000000000001510.

The selective neurokinin 3 receptor antagonist fezolinetant was a well tolerated and effective nonhormone therapy for moderate to severe vasomotor symptoms associated with menopause, Graeme L. Fraser, PhD, of Ogeda, a subsidiary of Astellas Pharma, and associates reported in Menopause.

yacobchuk/Getty Images

The investigators conducted a randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study between July 19, 2017, and Sept. 19, 2018, in 287 women who completed the full 12-week trial. The women were aged between 41 and 65 years, were menopausal, and had moderate to severe vasomotor symptoms (VMS) with an incidence of at least 50 episodes per week. The majority of the women were white, 25% were black, 1% were Asian, and 1% were “other.”

The reduction in VMS episodes in patients who received fezolinetant ranged from 1.9 to 3.5 episodes per day at week 4 and from 1.8 to 2.6 per day at week 12. The mean difference from placebo in VMS severity score was –0.4 to –1 at week 4 and was –0.2 to –0.6 at week 12. At least a 50% reduction in VMS frequency at week 12 was achieved by 81%-95% of patients who received fezolinetant, compared with 59% of those who received placebo.

Treatment-emergent adverse events were generally mild to moderate, with the most common events including nausea, diarrhea, fatigue, urinary tract infection, upper respiratory tract infections, sinusitis, headache, and cough. Of the five severe adverse events reported, only two were considered related to treatment – cholelithiasis and drug-induced liver injury. A total of 21 patients discontinued because of adverse events.

“Further evaluation of fezolinetant in larger and longer phase 3 trials of women with VMS associated with menopause is warranted to more fully characterize its efficacy and safety profile,” Dr. Fraser and colleagues concluded.

The study was funded by Astellas Pharma. The investigators reported numerous conflicts of interest with pharmaceutical companies.

[email protected]

SOURCE: Fraser GL et al. Menopause. 2020 Feb 24. doi: 10.1097/GME.0000000000001510.

GRAPEVINE, TEXAS – Higher body mass index is not associated with increased morbidity in women undergoing postpartum tubal ligation, according to a study of more than 1,000 patients.

Jake Remaly/MDedge News

“Even among patients within the highest BMI category, postpartum sterilization remains a safe and reasonable option,” John J. Byrne, MD, said at the Pregnancy Meeting. Dr. Byrne is affiliated with the department of obstetrics and gynecology at University of Texas Southwestern Medical Center in Dallas.

Physicians may recommend contraception within 6 weeks of delivery, but many patients do not attend postpartum visits. “One option for women who have completed childbearing is bilateral midsegment salpingectomy via minilaparotomy,” Dr. Byrne said at the Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine. “Offering this procedure immediately after delivery makes it available to women who face obstacles to follow-up care.”

The procedure entails the risk of anesthetic complications, bowel injury, and vascular injury. Subsequent pregnancy or ectopic pregnancy also may occur. Some centers will not perform the procedure if a patient’s size affects the surgeon’s ability to feel the relevant anatomy, Dr. Byrne said. “Although operative complications are presumed to be higher among obese women,” prior studies have not examined whether BMI affects rates of procedure completion, complication, or subsequent pregnancy, the researchers said.

To study this question, Dr. Byrne and colleagues examined data from women who requested postpartum sterilization following vaginal delivery at their center in 2018. The center uses the Parkland tubal ligation technique. The researchers assessed complication rates using a composite measure that included surgical complications (that is, blood transfusion, aborted procedure, or extension of incision), anesthetic complications, readmission, superficial or deep wound infection, venous thromboembolism, ileus or small bowel obstruction, incomplete transection, and subsequent pregnancy. The investigators used statistical tests to assess the relationship between BMI and morbidity.

In all, 1,014 patients underwent a postpartum tubal ligation; 17% had undergone prior abdominal surgery. The researchers classified patients’ BMI as normal (7% of the population), overweight (28%), class I obesity (38%), class II obesity (18%), or class III obesity (9%). A composite morbidity event occurred in 2%, and the proportion of patients with a complication did not significantly differ across BMI categories. No morbid events occurred in patients with normal BMI, which indicates “minimal risk” in this population, Dr. Byrne said. One incomplete transection occurred in a patient with class I obesity, and one subsequent pregnancy occurred in a patient with class II obesity. Estimated blood loss ranged from 9 mL in patients with normal BMI to 13 mL in patients with class III obesity, and length of surgery ranged from 32 minutes to 40 minutes. Neither difference is clinically significant, Dr. Byrne said.

“For the woman who desires permanent contraception, BMI should not impede her access to the procedure,” he noted.

The researchers had no relevant disclosures.

[email protected]

SOURCE: Byrne JJ et al. Am J Obstet Gynecol. 2020 Jan;222(1):S290, Abstract 442.

GRAPEVINE, TEXAS – Higher body mass index is not associated with increased morbidity in women undergoing postpartum tubal ligation, according to a study of more than 1,000 patients.

Jake Remaly/MDedge News

“Even among patients within the highest BMI category, postpartum sterilization remains a safe and reasonable option,” John J. Byrne, MD, said at the Pregnancy Meeting. Dr. Byrne is affiliated with the department of obstetrics and gynecology at University of Texas Southwestern Medical Center in Dallas.

Physicians may recommend contraception within 6 weeks of delivery, but many patients do not attend postpartum visits. “One option for women who have completed childbearing is bilateral midsegment salpingectomy via minilaparotomy,” Dr. Byrne said at the Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine. “Offering this procedure immediately after delivery makes it available to women who face obstacles to follow-up care.”

The procedure entails the risk of anesthetic complications, bowel injury, and vascular injury. Subsequent pregnancy or ectopic pregnancy also may occur. Some centers will not perform the procedure if a patient’s size affects the surgeon’s ability to feel the relevant anatomy, Dr. Byrne said. “Although operative complications are presumed to be higher among obese women,” prior studies have not examined whether BMI affects rates of procedure completion, complication, or subsequent pregnancy, the researchers said.

To study this question, Dr. Byrne and colleagues examined data from women who requested postpartum sterilization following vaginal delivery at their center in 2018. The center uses the Parkland tubal ligation technique. The researchers assessed complication rates using a composite measure that included surgical complications (that is, blood transfusion, aborted procedure, or extension of incision), anesthetic complications, readmission, superficial or deep wound infection, venous thromboembolism, ileus or small bowel obstruction, incomplete transection, and subsequent pregnancy. The investigators used statistical tests to assess the relationship between BMI and morbidity.

In all, 1,014 patients underwent a postpartum tubal ligation; 17% had undergone prior abdominal surgery. The researchers classified patients’ BMI as normal (7% of the population), overweight (28%), class I obesity (38%), class II obesity (18%), or class III obesity (9%). A composite morbidity event occurred in 2%, and the proportion of patients with a complication did not significantly differ across BMI categories. No morbid events occurred in patients with normal BMI, which indicates “minimal risk” in this population, Dr. Byrne said. One incomplete transection occurred in a patient with class I obesity, and one subsequent pregnancy occurred in a patient with class II obesity. Estimated blood loss ranged from 9 mL in patients with normal BMI to 13 mL in patients with class III obesity, and length of surgery ranged from 32 minutes to 40 minutes. Neither difference is clinically significant, Dr. Byrne said.

“For the woman who desires permanent contraception, BMI should not impede her access to the procedure,” he noted.

The researchers had no relevant disclosures.

[email protected]

SOURCE: Byrne JJ et al. Am J Obstet Gynecol. 2020 Jan;222(1):S290, Abstract 442.

GRAPEVINE, TEXAS – Higher body mass index is not associated with increased morbidity in women undergoing postpartum tubal ligation, according to a study of more than 1,000 patients.

Jake Remaly/MDedge News

“Even among patients within the highest BMI category, postpartum sterilization remains a safe and reasonable option,” John J. Byrne, MD, said at the Pregnancy Meeting. Dr. Byrne is affiliated with the department of obstetrics and gynecology at University of Texas Southwestern Medical Center in Dallas.

Physicians may recommend contraception within 6 weeks of delivery, but many patients do not attend postpartum visits. “One option for women who have completed childbearing is bilateral midsegment salpingectomy via minilaparotomy,” Dr. Byrne said at the Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine. “Offering this procedure immediately after delivery makes it available to women who face obstacles to follow-up care.”

The procedure entails the risk of anesthetic complications, bowel injury, and vascular injury. Subsequent pregnancy or ectopic pregnancy also may occur. Some centers will not perform the procedure if a patient’s size affects the surgeon’s ability to feel the relevant anatomy, Dr. Byrne said. “Although operative complications are presumed to be higher among obese women,” prior studies have not examined whether BMI affects rates of procedure completion, complication, or subsequent pregnancy, the researchers said.

To study this question, Dr. Byrne and colleagues examined data from women who requested postpartum sterilization following vaginal delivery at their center in 2018. The center uses the Parkland tubal ligation technique. The researchers assessed complication rates using a composite measure that included surgical complications (that is, blood transfusion, aborted procedure, or extension of incision), anesthetic complications, readmission, superficial or deep wound infection, venous thromboembolism, ileus or small bowel obstruction, incomplete transection, and subsequent pregnancy. The investigators used statistical tests to assess the relationship between BMI and morbidity.

In all, 1,014 patients underwent a postpartum tubal ligation; 17% had undergone prior abdominal surgery. The researchers classified patients’ BMI as normal (7% of the population), overweight (28%), class I obesity (38%), class II obesity (18%), or class III obesity (9%). A composite morbidity event occurred in 2%, and the proportion of patients with a complication did not significantly differ across BMI categories. No morbid events occurred in patients with normal BMI, which indicates “minimal risk” in this population, Dr. Byrne said. One incomplete transection occurred in a patient with class I obesity, and one subsequent pregnancy occurred in a patient with class II obesity. Estimated blood loss ranged from 9 mL in patients with normal BMI to 13 mL in patients with class III obesity, and length of surgery ranged from 32 minutes to 40 minutes. Neither difference is clinically significant, Dr. Byrne said.

“For the woman who desires permanent contraception, BMI should not impede her access to the procedure,” he noted.

The researchers had no relevant disclosures.

[email protected]

SOURCE: Byrne JJ et al. Am J Obstet Gynecol. 2020 Jan;222(1):S290, Abstract 442.

When she was 4 months pregnant, Angela Crawley waited for 30 minutes in a private room to hear the results of her noninvasive prenatal testing. Her ultrasound had been flagged as high risk by the radiologist and she agreed to undergo further testing to gather information on the health of her unborn child.

As she waited for her genetic counseling appointment, she noticed somber expressions on the faces of her health team and picked up on hushed tones.

It had taken 2 years to become pregnant and the joy she felt attending prenatal care appointments was fading into a sense of dread as she sat in that small room and the minutes ticked by.

Crawley – a scientist in the chronic disease program at the Ottawa Hospital Research Institute, assistant professor at the University of Ottawa, and adjunct research professor at Carleton University in Ontario, Canada – is more qualified than most patients to absorb health information and make appropriate decisions.

And yet, “I was completely unprepared,” she told Medscape Medical News as she reflected on what she now refers to as some of the darkest days of her life. “It was a nightmare and it was such a confusing, scary time.”

Crawley is among the more than 6 million women from at least 90 countries who have undergone noninvasive prenatal testing. During pregnancy, a mother’s bloodstream contains a mix of cell-free DNA from her own cells and from placental cells, which is usually identical to the DNA of the fetus. Analysis of cell-free DNA can lead to the early detection of genetic disorders.

Testing is most often used to look for chromosomal disorders that are caused by the presence of an extra chromosome, like in trisomy 21 in the case of Down syndrome or extra or missing copies of the X and Y chromosomes in other disorders. The accuracy of the test tends to vary, depending on the condition being assessed.

Cell-free DNA testing has reduced the number of invasive prenatal diagnostic procedures, some of which can lead to miscarriage, and this noninvasive option made sense to Crawley and was covered by government health insurance.

With a market projected to surpass $13 billion by the year 2027, some experts speculate that prenatal genetic testing is the most rapidly adopted test in human history. Globally, noninvasive prenatal tests cost $500 to $3,000 for patients who pay out of pocket, and all those screening options are amassing valuable genetic data troves.

The pioneer of noninvasive prenatal testing, Dennis Lo, PhD, from the Chinese University of Hong Kong, told Medscape Medical News that the success of using cell-free DNA came after a long, winding road of rejected grant applications and scientific skepticism.

“Initially, people did not think this would be useful for assessing chromosomal abnormalities because the thinking at the time was that we would need to count them,” Lo said.

But he was enchanted by early glimpses of the capability of cell-free DNA, and felt driven to pursue unconventional research ideas even though there were significant hurdles to overcome in the lab.

“We were detecting fetal Y chromosomes in women. At first, it was just scientific curiosity,” said Lo. “At the time, people worried that fetal cells would persist from one pregnancy to the next, but we discovered that fetal DNA actually clears very quickly and does not progress into the next pregnancy,” he explained. “This is very important because it won’t alter the accuracy of the test.”

Gripped by the scientific mystery, the researcher put in long hours at the lab. “I’m fortunate I have a very understanding wife who is herself a scientist,” he said. After a particularly long stretch without quality time together, Lo and his spouse, Alice Wong, went to see a Harry Potter movie.

As Lo viewed the Harry Potter H through 3D glasses, he was suddenly reminded of the male human karyotype.

“I saw the vertical stripes of the H and it hit me,” he told Medscape Medical News. “There are two sets of chromosomes.” The average human karyotype contains 22 pairs of autosomal chromosomes and one pair of sex chromosomes.

“Our complex genetic conundrum was cracked in the middle of a Harry Potter movie in a moment when I felt completely relaxed,” he recalled. “My wife said: ‘You can’t even watch a movie properly.’ ”

Back at the lab, Lo shared his Harry Potter–inspired concept and the team got to work.

In December 2019, Lo received the Fudan-Zhongzhi Science Award in Shanghai from Nobel laureate physicist Samuel Chao Chung Ting, chair of the award committee. The prize honors fundamental and groundbreaking achievements in biomedicine, and the laureate receives ¥3 million (about U.S. $428,550), donated by Zhongzhi Enterprise Group.

This honor was 30 years in the making, Lo told Medscape Medical News. “I’m pleased to experience public recognition and this is a high honor in China,” he added.

“Noninvasive prenatal testing is better than anything we’ve ever had before,” said Ronald Wapner, MD, from the Columbia University Irving Medical Center in New York City, who taught a course on the transition of prenatal diagnostics from amniocentesis to whole-genome sequencing at the recent Society for Maternal–Fetal Medicine 2020 Annual Pregnancy Meeting.

“We now have the capability to improve healthcare decision-making in utero and at birth,” he told Medscape Medical News. “It’s remarkable.”

But, Wapner said, the market grew too fast. “The National Institutes of Health didn’t even play a role in these fast-paced developments. Traditional governing bodies and authorities were bypassed as cytogenetic labs marketed directly to physicians and patients,” he explained.

One of the major problems with the rapid uptake in testing is a lack of preparation for patients like Crawley.

The clinician who delivered her test results was not feeling well, so “she spoke through a surgical mask,” Crawley reported. “I was trying to understand what she was saying, but it was an uncomfortable exchange.”

Crawley had undergone prenatal genetic testing because her ultrasound had shown irregularities in fetal leg measurements. The genetic tests confirmed no anomalies in the chromosome count, but that was it.

“There was no prognosis, just vague numbers that no one seemed to know what to do with,” Crawley recalled.

With concern about growth measurements, the conversation moved quickly to options, including termination. Crawley said the dialogue felt jarring and moved too quickly for her to process all the information and possible courses of action.

She was told she could terminate and “try again to get pregnant.” But Crawley was 39 years old and had been trying to conceive for 2 years.

“It was devastating,” she said. “No one sat down with me before this appointment to learn about my values or preferences, and I left that conversation with more questions than I had before I arrived. I went home and had one the worst weekends of my life. My husband and I felt so overwhelmed, grieved, and alone.”

Pretest counseling can be as important as any subsequent genetic counseling, said Blair Stevens, a prenatal expert from the National Society of Genetic Counselors and a genetic counselor at the University of Texas Health Science Center in Houston.

“Information is valuable, but it can also be toxic, depending on what individuals intend to do with what they learn,” she explained. “We cannot unknow or unhear details, so it’s really important to work with patients in advance to make sure their preferences guide any planning.”

Uncertainty can be very unsettling, she acknowledged. “It’s important to help patients balance any ambiguity, so if there is a 20% risk, there is also an 80% chance of another, perhaps more favorable, outcome.”

Most clinicians don’t have the time to fully assess patient goals and align counseling approaches to individual needs, Stevens explained. And public interest in prenatal testing has outpaced clinical best practices as competing labs race to expand offerings and add options to screening tests to grab a piece of the global market, which is now about 130 million births per year.

“These are not scientifically sound additions and we need more evidence,” Stevens said. “There is a right way to handle this, and labs and clinicians need to collaborate on responsible methods to test and integrate expanding options.”
 

The blue and pink elephant in the room

“The reality is that most people don’t have a super high risk for chromosomal irregularities,” said Stevens. “Most people are more interested in learning the sex of their baby in early pregnancy than in any actual desire for genetic information.” Noninvasive prenatal testing can detect fetal sex as early as 9 weeks into a pregnancy, whereas ultrasound might not detect it until about 18 weeks.

“Honestly? I think the growing popularity of gender-reveal parties is what is actually driving the push for more prenatal testing,” she added. “The problem is that a couple eager to learn the sex of their baby may wind up with way more information than they expected and have trouble processing unanticipated risk.”

In February, five national medical organizations in the United States partnered with the Reproductive Genetics Technology Consortium to develop consensus recommendations and guidelines for prenatal genetic testing.

The National Society of Genetic Counselors and the Society for Maternal–Fetal Medicine are among the new members that will provide a forum through which commercial laboratories can communicate about new technologies and obtain input and guidance on emerging options.

Wapner, who is a member of the consortium, said he hopes thought leaders will be at the forefront to guide this next chapter of prenatal screening. “So much money is pouring into all this testing; let’s make sure we are making the right, most essential screening decisions,” he said.

“Science typically advances more rapidly than the ethical and legal framework to support decision-making, and it’s important for society to put protections in place,” Lo acknowledged.

The misuse of screening and unethical sex-selection efforts in Asia and elsewhere in the world, where males are highly valued and females are more likely to be aborted, is dismaying, he told Medscape Medical News. “These are exploitations of the science.”

In addition to scientific misuse like sex selection, data breaches are becoming a huge concern as companies amass large amounts of valuable genetic information.
 

Data for ransom

In Canada, where Crawley took her test, LifeLabs – the country’s largest laboratory testing company and a provider of genetic testing – paid a ransom after a major cyberattack led to the theft of lab results for 85,000 people in Ontario and the personal information of 15 million customers.

LifeLabs paid an undisclosed sum to retrieve the data, the company reported on December 17, and hired cybersecurity experts to assess the damage. The company is offering security protection services, including identity theft and fraud protection insurance, to customers.

“This has served as a reminder that we need to stay ahead of cybercrime, which has become a pervasive issue around the world in all sectors,” Charles Brown, president and chief executive officer of LifeLabs, wrote in a letter to customers. “You entrust us with important health information, and we take that responsibility very seriously.”

The United States has led the world in the commercial push for more prenatal testing. Other countries in Europe, for example, have proceeded with caution and have integrated the technologies with more controls. Hong Kong, where the inventor of the test is based, has been among the slowest to adopt the practice.

“I have been lobbying for 8 years for Hong Kong to offer testing,” said Lo. “I think Hong Kong has been too slow to integrate, but the United States probably moved too quickly. There is a balance that I think countries like the Netherlands have found; they take the aim of screening into account, along with justice and societal aspects.”

“Ideally, we will develop a great pretest model triage tool to help guide patients through this process,” Stevens said. “And we have to make sure the data they receive are clinically useful and backed up by evidence to safeguard the care of every patient.”

The practice of medicine is meticulously designed to assess and mitigate risk, “but this sensible objective can also be extremely negative in focus, with not-so-great delivery of information,” she acknowledged. Each individual’s tolerance for uncertainty and ability to cope in the face of adversity varies. “These are complex conversations that require time and empathy, and the details matter,” she added.

“In my home state of Texas, where there is a large religious base, there is not as much drive for advance prenatal genetic information,” Stevens explained. “We see a real advocacy movement emerging and a need for information from patients first because these can’t really be clinician-led decisions,” she pointed out. “Patients come to us undergoing not just the physical changes of pregnancy, but also emotional transformation as they transition to become parents. They may be nauseous or already sleep-deprived and they need our help,” she added.

Crawley could feel the fluttering of fetal movements in her womb and said she felt connected to her child, but she remembered her trip to Ireland when she and her husband drank too much and they likely conceived. Irrational thoughts crept in: “Maybe it was something we did. What about my swimming; could it have been harmful?”

Apprehensions lingered as she waited to meet her specialist. Would the child grow and be able to walk? Be held back by disabling joint pain? Crawley sat down with her doctor at the high-risk clinic to discuss the possibilities.

“I don’t see anything to be alarmed about. She’s probably going to be small,” said the obstetrician.

“She?!” Crawley had opted not to learn the sex of her baby, unlike so many other parents she knew, but her hope for her baby’s good health soared above the accidental disclosure.

“Everything changed in that moment,” Crawley said. “I knew that we were going to be okay no matter what happened next.”

Crawley’s pregnancy progressed to term and she gave birth to a healthy baby girl who is now 3 years old and dances ballet. Her beloved daughter is shorter than some of the other dancers in her class, but her mom says she hasn’t missed a beat. “The world is a better place because my daughter is in it,” Crawley said. “This, I know for sure.”

This article first appeared on Medscape.com.

When she was 4 months pregnant, Angela Crawley waited for 30 minutes in a private room to hear the results of her noninvasive prenatal testing. Her ultrasound had been flagged as high risk by the radiologist and she agreed to undergo further testing to gather information on the health of her unborn child.

As she waited for her genetic counseling appointment, she noticed somber expressions on the faces of her health team and picked up on hushed tones.

It had taken 2 years to become pregnant and the joy she felt attending prenatal care appointments was fading into a sense of dread as she sat in that small room and the minutes ticked by.

Crawley – a scientist in the chronic disease program at the Ottawa Hospital Research Institute, assistant professor at the University of Ottawa, and adjunct research professor at Carleton University in Ontario, Canada – is more qualified than most patients to absorb health information and make appropriate decisions.

And yet, “I was completely unprepared,” she told Medscape Medical News as she reflected on what she now refers to as some of the darkest days of her life. “It was a nightmare and it was such a confusing, scary time.”

Crawley is among the more than 6 million women from at least 90 countries who have undergone noninvasive prenatal testing. During pregnancy, a mother’s bloodstream contains a mix of cell-free DNA from her own cells and from placental cells, which is usually identical to the DNA of the fetus. Analysis of cell-free DNA can lead to the early detection of genetic disorders.

Testing is most often used to look for chromosomal disorders that are caused by the presence of an extra chromosome, like in trisomy 21 in the case of Down syndrome or extra or missing copies of the X and Y chromosomes in other disorders. The accuracy of the test tends to vary, depending on the condition being assessed.

Cell-free DNA testing has reduced the number of invasive prenatal diagnostic procedures, some of which can lead to miscarriage, and this noninvasive option made sense to Crawley and was covered by government health insurance.

With a market projected to surpass $13 billion by the year 2027, some experts speculate that prenatal genetic testing is the most rapidly adopted test in human history. Globally, noninvasive prenatal tests cost $500 to $3,000 for patients who pay out of pocket, and all those screening options are amassing valuable genetic data troves.

The pioneer of noninvasive prenatal testing, Dennis Lo, PhD, from the Chinese University of Hong Kong, told Medscape Medical News that the success of using cell-free DNA came after a long, winding road of rejected grant applications and scientific skepticism.

“Initially, people did not think this would be useful for assessing chromosomal abnormalities because the thinking at the time was that we would need to count them,” Lo said.

But he was enchanted by early glimpses of the capability of cell-free DNA, and felt driven to pursue unconventional research ideas even though there were significant hurdles to overcome in the lab.

“We were detecting fetal Y chromosomes in women. At first, it was just scientific curiosity,” said Lo. “At the time, people worried that fetal cells would persist from one pregnancy to the next, but we discovered that fetal DNA actually clears very quickly and does not progress into the next pregnancy,” he explained. “This is very important because it won’t alter the accuracy of the test.”

Gripped by the scientific mystery, the researcher put in long hours at the lab. “I’m fortunate I have a very understanding wife who is herself a scientist,” he said. After a particularly long stretch without quality time together, Lo and his spouse, Alice Wong, went to see a Harry Potter movie.

As Lo viewed the Harry Potter H through 3D glasses, he was suddenly reminded of the male human karyotype.

“I saw the vertical stripes of the H and it hit me,” he told Medscape Medical News. “There are two sets of chromosomes.” The average human karyotype contains 22 pairs of autosomal chromosomes and one pair of sex chromosomes.

“Our complex genetic conundrum was cracked in the middle of a Harry Potter movie in a moment when I felt completely relaxed,” he recalled. “My wife said: ‘You can’t even watch a movie properly.’ ”

Back at the lab, Lo shared his Harry Potter–inspired concept and the team got to work.

In December 2019, Lo received the Fudan-Zhongzhi Science Award in Shanghai from Nobel laureate physicist Samuel Chao Chung Ting, chair of the award committee. The prize honors fundamental and groundbreaking achievements in biomedicine, and the laureate receives ¥3 million (about U.S. $428,550), donated by Zhongzhi Enterprise Group.

This honor was 30 years in the making, Lo told Medscape Medical News. “I’m pleased to experience public recognition and this is a high honor in China,” he added.

“Noninvasive prenatal testing is better than anything we’ve ever had before,” said Ronald Wapner, MD, from the Columbia University Irving Medical Center in New York City, who taught a course on the transition of prenatal diagnostics from amniocentesis to whole-genome sequencing at the recent Society for Maternal–Fetal Medicine 2020 Annual Pregnancy Meeting.

“We now have the capability to improve healthcare decision-making in utero and at birth,” he told Medscape Medical News. “It’s remarkable.”

But, Wapner said, the market grew too fast. “The National Institutes of Health didn’t even play a role in these fast-paced developments. Traditional governing bodies and authorities were bypassed as cytogenetic labs marketed directly to physicians and patients,” he explained.

One of the major problems with the rapid uptake in testing is a lack of preparation for patients like Crawley.

The clinician who delivered her test results was not feeling well, so “she spoke through a surgical mask,” Crawley reported. “I was trying to understand what she was saying, but it was an uncomfortable exchange.”

Crawley had undergone prenatal genetic testing because her ultrasound had shown irregularities in fetal leg measurements. The genetic tests confirmed no anomalies in the chromosome count, but that was it.

“There was no prognosis, just vague numbers that no one seemed to know what to do with,” Crawley recalled.

With concern about growth measurements, the conversation moved quickly to options, including termination. Crawley said the dialogue felt jarring and moved too quickly for her to process all the information and possible courses of action.

She was told she could terminate and “try again to get pregnant.” But Crawley was 39 years old and had been trying to conceive for 2 years.

“It was devastating,” she said. “No one sat down with me before this appointment to learn about my values or preferences, and I left that conversation with more questions than I had before I arrived. I went home and had one the worst weekends of my life. My husband and I felt so overwhelmed, grieved, and alone.”

Pretest counseling can be as important as any subsequent genetic counseling, said Blair Stevens, a prenatal expert from the National Society of Genetic Counselors and a genetic counselor at the University of Texas Health Science Center in Houston.

“Information is valuable, but it can also be toxic, depending on what individuals intend to do with what they learn,” she explained. “We cannot unknow or unhear details, so it’s really important to work with patients in advance to make sure their preferences guide any planning.”

Uncertainty can be very unsettling, she acknowledged. “It’s important to help patients balance any ambiguity, so if there is a 20% risk, there is also an 80% chance of another, perhaps more favorable, outcome.”

Most clinicians don’t have the time to fully assess patient goals and align counseling approaches to individual needs, Stevens explained. And public interest in prenatal testing has outpaced clinical best practices as competing labs race to expand offerings and add options to screening tests to grab a piece of the global market, which is now about 130 million births per year.

“These are not scientifically sound additions and we need more evidence,” Stevens said. “There is a right way to handle this, and labs and clinicians need to collaborate on responsible methods to test and integrate expanding options.”
 

The blue and pink elephant in the room

“The reality is that most people don’t have a super high risk for chromosomal irregularities,” said Stevens. “Most people are more interested in learning the sex of their baby in early pregnancy than in any actual desire for genetic information.” Noninvasive prenatal testing can detect fetal sex as early as 9 weeks into a pregnancy, whereas ultrasound might not detect it until about 18 weeks.

“Honestly? I think the growing popularity of gender-reveal parties is what is actually driving the push for more prenatal testing,” she added. “The problem is that a couple eager to learn the sex of their baby may wind up with way more information than they expected and have trouble processing unanticipated risk.”

In February, five national medical organizations in the United States partnered with the Reproductive Genetics Technology Consortium to develop consensus recommendations and guidelines for prenatal genetic testing.

The National Society of Genetic Counselors and the Society for Maternal–Fetal Medicine are among the new members that will provide a forum through which commercial laboratories can communicate about new technologies and obtain input and guidance on emerging options.

Wapner, who is a member of the consortium, said he hopes thought leaders will be at the forefront to guide this next chapter of prenatal screening. “So much money is pouring into all this testing; let’s make sure we are making the right, most essential screening decisions,” he said.

“Science typically advances more rapidly than the ethical and legal framework to support decision-making, and it’s important for society to put protections in place,” Lo acknowledged.

The misuse of screening and unethical sex-selection efforts in Asia and elsewhere in the world, where males are highly valued and females are more likely to be aborted, is dismaying, he told Medscape Medical News. “These are exploitations of the science.”

In addition to scientific misuse like sex selection, data breaches are becoming a huge concern as companies amass large amounts of valuable genetic information.
 

Data for ransom

In Canada, where Crawley took her test, LifeLabs – the country’s largest laboratory testing company and a provider of genetic testing – paid a ransom after a major cyberattack led to the theft of lab results for 85,000 people in Ontario and the personal information of 15 million customers.

LifeLabs paid an undisclosed sum to retrieve the data, the company reported on December 17, and hired cybersecurity experts to assess the damage. The company is offering security protection services, including identity theft and fraud protection insurance, to customers.

“This has served as a reminder that we need to stay ahead of cybercrime, which has become a pervasive issue around the world in all sectors,” Charles Brown, president and chief executive officer of LifeLabs, wrote in a letter to customers. “You entrust us with important health information, and we take that responsibility very seriously.”

The United States has led the world in the commercial push for more prenatal testing. Other countries in Europe, for example, have proceeded with caution and have integrated the technologies with more controls. Hong Kong, where the inventor of the test is based, has been among the slowest to adopt the practice.

“I have been lobbying for 8 years for Hong Kong to offer testing,” said Lo. “I think Hong Kong has been too slow to integrate, but the United States probably moved too quickly. There is a balance that I think countries like the Netherlands have found; they take the aim of screening into account, along with justice and societal aspects.”

“Ideally, we will develop a great pretest model triage tool to help guide patients through this process,” Stevens said. “And we have to make sure the data they receive are clinically useful and backed up by evidence to safeguard the care of every patient.”

The practice of medicine is meticulously designed to assess and mitigate risk, “but this sensible objective can also be extremely negative in focus, with not-so-great delivery of information,” she acknowledged. Each individual’s tolerance for uncertainty and ability to cope in the face of adversity varies. “These are complex conversations that require time and empathy, and the details matter,” she added.

“In my home state of Texas, where there is a large religious base, there is not as much drive for advance prenatal genetic information,” Stevens explained. “We see a real advocacy movement emerging and a need for information from patients first because these can’t really be clinician-led decisions,” she pointed out. “Patients come to us undergoing not just the physical changes of pregnancy, but also emotional transformation as they transition to become parents. They may be nauseous or already sleep-deprived and they need our help,” she added.

Crawley could feel the fluttering of fetal movements in her womb and said she felt connected to her child, but she remembered her trip to Ireland when she and her husband drank too much and they likely conceived. Irrational thoughts crept in: “Maybe it was something we did. What about my swimming; could it have been harmful?”

Apprehensions lingered as she waited to meet her specialist. Would the child grow and be able to walk? Be held back by disabling joint pain? Crawley sat down with her doctor at the high-risk clinic to discuss the possibilities.

“I don’t see anything to be alarmed about. She’s probably going to be small,” said the obstetrician.

“She?!” Crawley had opted not to learn the sex of her baby, unlike so many other parents she knew, but her hope for her baby’s good health soared above the accidental disclosure.

“Everything changed in that moment,” Crawley said. “I knew that we were going to be okay no matter what happened next.”

Crawley’s pregnancy progressed to term and she gave birth to a healthy baby girl who is now 3 years old and dances ballet. Her beloved daughter is shorter than some of the other dancers in her class, but her mom says she hasn’t missed a beat. “The world is a better place because my daughter is in it,” Crawley said. “This, I know for sure.”

This article first appeared on Medscape.com.

When she was 4 months pregnant, Angela Crawley waited for 30 minutes in a private room to hear the results of her noninvasive prenatal testing. Her ultrasound had been flagged as high risk by the radiologist and she agreed to undergo further testing to gather information on the health of her unborn child.

As she waited for her genetic counseling appointment, she noticed somber expressions on the faces of her health team and picked up on hushed tones.

It had taken 2 years to become pregnant and the joy she felt attending prenatal care appointments was fading into a sense of dread as she sat in that small room and the minutes ticked by.

Crawley – a scientist in the chronic disease program at the Ottawa Hospital Research Institute, assistant professor at the University of Ottawa, and adjunct research professor at Carleton University in Ontario, Canada – is more qualified than most patients to absorb health information and make appropriate decisions.

And yet, “I was completely unprepared,” she told Medscape Medical News as she reflected on what she now refers to as some of the darkest days of her life. “It was a nightmare and it was such a confusing, scary time.”

Crawley is among the more than 6 million women from at least 90 countries who have undergone noninvasive prenatal testing. During pregnancy, a mother’s bloodstream contains a mix of cell-free DNA from her own cells and from placental cells, which is usually identical to the DNA of the fetus. Analysis of cell-free DNA can lead to the early detection of genetic disorders.

Testing is most often used to look for chromosomal disorders that are caused by the presence of an extra chromosome, like in trisomy 21 in the case of Down syndrome or extra or missing copies of the X and Y chromosomes in other disorders. The accuracy of the test tends to vary, depending on the condition being assessed.

Cell-free DNA testing has reduced the number of invasive prenatal diagnostic procedures, some of which can lead to miscarriage, and this noninvasive option made sense to Crawley and was covered by government health insurance.

With a market projected to surpass $13 billion by the year 2027, some experts speculate that prenatal genetic testing is the most rapidly adopted test in human history. Globally, noninvasive prenatal tests cost $500 to $3,000 for patients who pay out of pocket, and all those screening options are amassing valuable genetic data troves.

The pioneer of noninvasive prenatal testing, Dennis Lo, PhD, from the Chinese University of Hong Kong, told Medscape Medical News that the success of using cell-free DNA came after a long, winding road of rejected grant applications and scientific skepticism.

“Initially, people did not think this would be useful for assessing chromosomal abnormalities because the thinking at the time was that we would need to count them,” Lo said.

But he was enchanted by early glimpses of the capability of cell-free DNA, and felt driven to pursue unconventional research ideas even though there were significant hurdles to overcome in the lab.

“We were detecting fetal Y chromosomes in women. At first, it was just scientific curiosity,” said Lo. “At the time, people worried that fetal cells would persist from one pregnancy to the next, but we discovered that fetal DNA actually clears very quickly and does not progress into the next pregnancy,” he explained. “This is very important because it won’t alter the accuracy of the test.”

Gripped by the scientific mystery, the researcher put in long hours at the lab. “I’m fortunate I have a very understanding wife who is herself a scientist,” he said. After a particularly long stretch without quality time together, Lo and his spouse, Alice Wong, went to see a Harry Potter movie.

As Lo viewed the Harry Potter H through 3D glasses, he was suddenly reminded of the male human karyotype.

“I saw the vertical stripes of the H and it hit me,” he told Medscape Medical News. “There are two sets of chromosomes.” The average human karyotype contains 22 pairs of autosomal chromosomes and one pair of sex chromosomes.

“Our complex genetic conundrum was cracked in the middle of a Harry Potter movie in a moment when I felt completely relaxed,” he recalled. “My wife said: ‘You can’t even watch a movie properly.’ ”

Back at the lab, Lo shared his Harry Potter–inspired concept and the team got to work.

In December 2019, Lo received the Fudan-Zhongzhi Science Award in Shanghai from Nobel laureate physicist Samuel Chao Chung Ting, chair of the award committee. The prize honors fundamental and groundbreaking achievements in biomedicine, and the laureate receives ¥3 million (about U.S. $428,550), donated by Zhongzhi Enterprise Group.

This honor was 30 years in the making, Lo told Medscape Medical News. “I’m pleased to experience public recognition and this is a high honor in China,” he added.

“Noninvasive prenatal testing is better than anything we’ve ever had before,” said Ronald Wapner, MD, from the Columbia University Irving Medical Center in New York City, who taught a course on the transition of prenatal diagnostics from amniocentesis to whole-genome sequencing at the recent Society for Maternal–Fetal Medicine 2020 Annual Pregnancy Meeting.

“We now have the capability to improve healthcare decision-making in utero and at birth,” he told Medscape Medical News. “It’s remarkable.”

But, Wapner said, the market grew too fast. “The National Institutes of Health didn’t even play a role in these fast-paced developments. Traditional governing bodies and authorities were bypassed as cytogenetic labs marketed directly to physicians and patients,” he explained.

One of the major problems with the rapid uptake in testing is a lack of preparation for patients like Crawley.

The clinician who delivered her test results was not feeling well, so “she spoke through a surgical mask,” Crawley reported. “I was trying to understand what she was saying, but it was an uncomfortable exchange.”

Crawley had undergone prenatal genetic testing because her ultrasound had shown irregularities in fetal leg measurements. The genetic tests confirmed no anomalies in the chromosome count, but that was it.

“There was no prognosis, just vague numbers that no one seemed to know what to do with,” Crawley recalled.

With concern about growth measurements, the conversation moved quickly to options, including termination. Crawley said the dialogue felt jarring and moved too quickly for her to process all the information and possible courses of action.

She was told she could terminate and “try again to get pregnant.” But Crawley was 39 years old and had been trying to conceive for 2 years.

“It was devastating,” she said. “No one sat down with me before this appointment to learn about my values or preferences, and I left that conversation with more questions than I had before I arrived. I went home and had one the worst weekends of my life. My husband and I felt so overwhelmed, grieved, and alone.”

Pretest counseling can be as important as any subsequent genetic counseling, said Blair Stevens, a prenatal expert from the National Society of Genetic Counselors and a genetic counselor at the University of Texas Health Science Center in Houston.

“Information is valuable, but it can also be toxic, depending on what individuals intend to do with what they learn,” she explained. “We cannot unknow or unhear details, so it’s really important to work with patients in advance to make sure their preferences guide any planning.”

Uncertainty can be very unsettling, she acknowledged. “It’s important to help patients balance any ambiguity, so if there is a 20% risk, there is also an 80% chance of another, perhaps more favorable, outcome.”

Most clinicians don’t have the time to fully assess patient goals and align counseling approaches to individual needs, Stevens explained. And public interest in prenatal testing has outpaced clinical best practices as competing labs race to expand offerings and add options to screening tests to grab a piece of the global market, which is now about 130 million births per year.

“These are not scientifically sound additions and we need more evidence,” Stevens said. “There is a right way to handle this, and labs and clinicians need to collaborate on responsible methods to test and integrate expanding options.”
 

The blue and pink elephant in the room

“The reality is that most people don’t have a super high risk for chromosomal irregularities,” said Stevens. “Most people are more interested in learning the sex of their baby in early pregnancy than in any actual desire for genetic information.” Noninvasive prenatal testing can detect fetal sex as early as 9 weeks into a pregnancy, whereas ultrasound might not detect it until about 18 weeks.

“Honestly? I think the growing popularity of gender-reveal parties is what is actually driving the push for more prenatal testing,” she added. “The problem is that a couple eager to learn the sex of their baby may wind up with way more information than they expected and have trouble processing unanticipated risk.”

In February, five national medical organizations in the United States partnered with the Reproductive Genetics Technology Consortium to develop consensus recommendations and guidelines for prenatal genetic testing.

The National Society of Genetic Counselors and the Society for Maternal–Fetal Medicine are among the new members that will provide a forum through which commercial laboratories can communicate about new technologies and obtain input and guidance on emerging options.

Wapner, who is a member of the consortium, said he hopes thought leaders will be at the forefront to guide this next chapter of prenatal screening. “So much money is pouring into all this testing; let’s make sure we are making the right, most essential screening decisions,” he said.

“Science typically advances more rapidly than the ethical and legal framework to support decision-making, and it’s important for society to put protections in place,” Lo acknowledged.

The misuse of screening and unethical sex-selection efforts in Asia and elsewhere in the world, where males are highly valued and females are more likely to be aborted, is dismaying, he told Medscape Medical News. “These are exploitations of the science.”

In addition to scientific misuse like sex selection, data breaches are becoming a huge concern as companies amass large amounts of valuable genetic information.
 

Data for ransom

In Canada, where Crawley took her test, LifeLabs – the country’s largest laboratory testing company and a provider of genetic testing – paid a ransom after a major cyberattack led to the theft of lab results for 85,000 people in Ontario and the personal information of 15 million customers.

LifeLabs paid an undisclosed sum to retrieve the data, the company reported on December 17, and hired cybersecurity experts to assess the damage. The company is offering security protection services, including identity theft and fraud protection insurance, to customers.

“This has served as a reminder that we need to stay ahead of cybercrime, which has become a pervasive issue around the world in all sectors,” Charles Brown, president and chief executive officer of LifeLabs, wrote in a letter to customers. “You entrust us with important health information, and we take that responsibility very seriously.”

The United States has led the world in the commercial push for more prenatal testing. Other countries in Europe, for example, have proceeded with caution and have integrated the technologies with more controls. Hong Kong, where the inventor of the test is based, has been among the slowest to adopt the practice.

“I have been lobbying for 8 years for Hong Kong to offer testing,” said Lo. “I think Hong Kong has been too slow to integrate, but the United States probably moved too quickly. There is a balance that I think countries like the Netherlands have found; they take the aim of screening into account, along with justice and societal aspects.”

“Ideally, we will develop a great pretest model triage tool to help guide patients through this process,” Stevens said. “And we have to make sure the data they receive are clinically useful and backed up by evidence to safeguard the care of every patient.”

The practice of medicine is meticulously designed to assess and mitigate risk, “but this sensible objective can also be extremely negative in focus, with not-so-great delivery of information,” she acknowledged. Each individual’s tolerance for uncertainty and ability to cope in the face of adversity varies. “These are complex conversations that require time and empathy, and the details matter,” she added.

“In my home state of Texas, where there is a large religious base, there is not as much drive for advance prenatal genetic information,” Stevens explained. “We see a real advocacy movement emerging and a need for information from patients first because these can’t really be clinician-led decisions,” she pointed out. “Patients come to us undergoing not just the physical changes of pregnancy, but also emotional transformation as they transition to become parents. They may be nauseous or already sleep-deprived and they need our help,” she added.

Crawley could feel the fluttering of fetal movements in her womb and said she felt connected to her child, but she remembered her trip to Ireland when she and her husband drank too much and they likely conceived. Irrational thoughts crept in: “Maybe it was something we did. What about my swimming; could it have been harmful?”

Apprehensions lingered as she waited to meet her specialist. Would the child grow and be able to walk? Be held back by disabling joint pain? Crawley sat down with her doctor at the high-risk clinic to discuss the possibilities.

“I don’t see anything to be alarmed about. She’s probably going to be small,” said the obstetrician.

“She?!” Crawley had opted not to learn the sex of her baby, unlike so many other parents she knew, but her hope for her baby’s good health soared above the accidental disclosure.

“Everything changed in that moment,” Crawley said. “I knew that we were going to be okay no matter what happened next.”

Crawley’s pregnancy progressed to term and she gave birth to a healthy baby girl who is now 3 years old and dances ballet. Her beloved daughter is shorter than some of the other dancers in her class, but her mom says she hasn’t missed a beat. “The world is a better place because my daughter is in it,” Crawley said. “This, I know for sure.”

This article first appeared on Medscape.com.

Women who had experienced stillbirth were more than twice as likely to eventually develop end-stage renal disease (ESRD) than were those who had not, and they were also at greater risk for chronic kidney disease (CKD), according to findings published in the American Journal of Obstetrics & Gynecology.

Peter M Barrett, MB, of the University College Cork (Ireland), and colleagues conducted a population-based cohort study using data from the Swedish Medical Birth Register, National Patient Register, and the Swedish Renal Register to identify women who had live births and stillbirths. They then used anonymized unique personal identification numbers to cross-reference the registries.

From a full cohort of nearly 2 million women who gave birth during 1973-2012, and during a median follow-up of 20.7 years, 13,032 women experienced stillbirth, which, until 2008, was defined as fetal death after 28 weeks’ gestation, and after 2008, as occurring after 22 weeks. Women were excluded if they had any diagnosis of renal disease before their first pregnancy, as well as for a history of cardiovascular disease, chronic hypertension, diabetes, and certain other conditions at baseline.

Overall, 18,017 women developed CKD, and 1,283 developed ESRD. The fully adjusted model showed adjusted hazard ratios of 1.26 for CKD (95% confidence interval, 1.09-1.45) and 2.25 for ESRD (95% CI, 1.55-3.25) in women who had experienced stillbirth, compared with those who had not experienced stillbirth.

The researchers reported that associations between stillbirth and renal disease existed independently of underlying medical and obstetric comorbidities, such as congenital malformations, being small for gestational age, and preeclampsia, and that when those comorbidities were excluded, “the associations between stillbirth and maternal renal disease were strengthened (CKD: aHR, 1.33; 95% CI, 1.13-1.57; and ESRD: aHR, 2.95; 95% CI, 1.86-4.68).”

In addition, they noted that there was no significant association between stillbirth and either CKD or ESRD in women who had prepregnancy medical comorbidities (CKD: aHR, 1.13; 95% CI 0.73-1.75; and ESRD: aHR 1.49; 95% CI, 0.78-2.85).

“Further research is required to better understand the underlying pathophysiology of this association and to determine whether affected women would benefit from closer surveillance and follow-up for future hypertension and renal disease,” the authors concluded.

The work was performed within the Irish Clinical Academic Training Programme and was funded by grants from several organizations. The authors reported no conflicts of interest.

[email protected]

SOURCE: Barret PM et al. Am J Obstet Gynecol. 2020 Feb 26. doi: 10.1016/j.ajog.2020.02.031.

Women who had experienced stillbirth were more than twice as likely to eventually develop end-stage renal disease (ESRD) than were those who had not, and they were also at greater risk for chronic kidney disease (CKD), according to findings published in the American Journal of Obstetrics & Gynecology.

Peter M Barrett, MB, of the University College Cork (Ireland), and colleagues conducted a population-based cohort study using data from the Swedish Medical Birth Register, National Patient Register, and the Swedish Renal Register to identify women who had live births and stillbirths. They then used anonymized unique personal identification numbers to cross-reference the registries.

From a full cohort of nearly 2 million women who gave birth during 1973-2012, and during a median follow-up of 20.7 years, 13,032 women experienced stillbirth, which, until 2008, was defined as fetal death after 28 weeks’ gestation, and after 2008, as occurring after 22 weeks. Women were excluded if they had any diagnosis of renal disease before their first pregnancy, as well as for a history of cardiovascular disease, chronic hypertension, diabetes, and certain other conditions at baseline.

Overall, 18,017 women developed CKD, and 1,283 developed ESRD. The fully adjusted model showed adjusted hazard ratios of 1.26 for CKD (95% confidence interval, 1.09-1.45) and 2.25 for ESRD (95% CI, 1.55-3.25) in women who had experienced stillbirth, compared with those who had not experienced stillbirth.

The researchers reported that associations between stillbirth and renal disease existed independently of underlying medical and obstetric comorbidities, such as congenital malformations, being small for gestational age, and preeclampsia, and that when those comorbidities were excluded, “the associations between stillbirth and maternal renal disease were strengthened (CKD: aHR, 1.33; 95% CI, 1.13-1.57; and ESRD: aHR, 2.95; 95% CI, 1.86-4.68).”

In addition, they noted that there was no significant association between stillbirth and either CKD or ESRD in women who had prepregnancy medical comorbidities (CKD: aHR, 1.13; 95% CI 0.73-1.75; and ESRD: aHR 1.49; 95% CI, 0.78-2.85).

“Further research is required to better understand the underlying pathophysiology of this association and to determine whether affected women would benefit from closer surveillance and follow-up for future hypertension and renal disease,” the authors concluded.

The work was performed within the Irish Clinical Academic Training Programme and was funded by grants from several organizations. The authors reported no conflicts of interest.

[email protected]

SOURCE: Barret PM et al. Am J Obstet Gynecol. 2020 Feb 26. doi: 10.1016/j.ajog.2020.02.031.

Women who had experienced stillbirth were more than twice as likely to eventually develop end-stage renal disease (ESRD) than were those who had not, and they were also at greater risk for chronic kidney disease (CKD), according to findings published in the American Journal of Obstetrics & Gynecology.

Peter M Barrett, MB, of the University College Cork (Ireland), and colleagues conducted a population-based cohort study using data from the Swedish Medical Birth Register, National Patient Register, and the Swedish Renal Register to identify women who had live births and stillbirths. They then used anonymized unique personal identification numbers to cross-reference the registries.

From a full cohort of nearly 2 million women who gave birth during 1973-2012, and during a median follow-up of 20.7 years, 13,032 women experienced stillbirth, which, until 2008, was defined as fetal death after 28 weeks’ gestation, and after 2008, as occurring after 22 weeks. Women were excluded if they had any diagnosis of renal disease before their first pregnancy, as well as for a history of cardiovascular disease, chronic hypertension, diabetes, and certain other conditions at baseline.

Overall, 18,017 women developed CKD, and 1,283 developed ESRD. The fully adjusted model showed adjusted hazard ratios of 1.26 for CKD (95% confidence interval, 1.09-1.45) and 2.25 for ESRD (95% CI, 1.55-3.25) in women who had experienced stillbirth, compared with those who had not experienced stillbirth.

The researchers reported that associations between stillbirth and renal disease existed independently of underlying medical and obstetric comorbidities, such as congenital malformations, being small for gestational age, and preeclampsia, and that when those comorbidities were excluded, “the associations between stillbirth and maternal renal disease were strengthened (CKD: aHR, 1.33; 95% CI, 1.13-1.57; and ESRD: aHR, 2.95; 95% CI, 1.86-4.68).”

In addition, they noted that there was no significant association between stillbirth and either CKD or ESRD in women who had prepregnancy medical comorbidities (CKD: aHR, 1.13; 95% CI 0.73-1.75; and ESRD: aHR 1.49; 95% CI, 0.78-2.85).

“Further research is required to better understand the underlying pathophysiology of this association and to determine whether affected women would benefit from closer surveillance and follow-up for future hypertension and renal disease,” the authors concluded.

The work was performed within the Irish Clinical Academic Training Programme and was funded by grants from several organizations. The authors reported no conflicts of interest.

[email protected]

SOURCE: Barret PM et al. Am J Obstet Gynecol. 2020 Feb 26. doi: 10.1016/j.ajog.2020.02.031.

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

PHOENIX – The level of physical activity people engage in during their golden years doesn’t have to be strenuous in order to be effective, results from two studies presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting showed.

Courtesy University of California, San Diego

In one study, women who walked 2,100-4,500 steps each day reduced their risk of dying from cardiovascular disease by up to 38%, compared with those who walked fewer than 2,100 steps each day. In addition, women who walked more than 4,500 steps each day reduced their risk of cardiovascular disease (CVD) mortality risk by 48%.

The findings come from an ancillary analysis of the Women’s Health Study known as the Objective Physical Activity and Cardiovascular Health (OPACH) Study.

“Our work shows that both light-intensity and moderate-/vigorous-intensity steps are associated with reduced risk of cardiovascular disease death,” lead author Andrea Z. LaCroix, PhD, said in an interview. “And our previous studies show that all movement while standing, stepping, or just moving about at whatever intensity you choose, appears to have cardiovascular benefits, whereas long hours spent sedentary, especially prolonged sitting bouts are associated with increased risk of cardiovascular disease. These new findings on steps are best interpreted as showing that moving instead of sitting is good for your heart and blood vessels as we get older. Find the things you love to do and get moving.”

For OPACH, 6,379 women with an average age of 79 years wore ActiGraph GT3X+ triaxial accelerometers on their wrist for 7 days during 2012-2014, as a way to ascertain the number of steps they took. The researchers followed the study participants to March 1, 2019, and used Cox proportional hazard models to estimate CVD mortality across four quartiles of steps per day, adjusted for age, race/ethnicity, education, smoking, alcohol consumption, self-reported health, comorbidities, and physical function. The lowest quartile reference category was less than 2,108 steps per day. The second, third and fourth quartiles were: 2,108 to fewer than 3,136 steps, 3,136 to fewer than 4,499, and 4,500 and above.

Dr. LaCroix, distinguished professor and chief of epidemiology at the University of California, San Diego, reported that women who walked 2,100-4,500 steps daily reduced their risk of dying from CVD by up to up to 38%, compared with women who walked fewer than 2,100 daily steps. The women who walked more than 4,500 steps per day reduced their risk by 48%.

She noted that, for many years, common wisdom was that 10,000 steps per day should be used as a general fitness target, [but] that goal “was never evidence based, and so far, emerging evidence using accelerometers to measure steps shows benefit way below the level of 10,000 steps.” Dr. LaCroix added that, in this study, “we were able separate steps taken at a light intensity of energy expenditure versus a moderate or vigorous level of energy expenditure. This is like comparing slower versus faster steps. Both influenced the risk of CVD death and we found no evidence that faster steps were more beneficial for reducing risk of CVD death than slower steps. So, the main message I want my demographic [women aged over 60] to understand is that all movement appears to be good for your heart.”

Barry A. Franklin, PhD, director of preventive cardiology and cardiac rehabilitation at Beaumont Health in Royal Oak, Mich., characterized the study findings as “good news” but not entirely surprising. “It goes along with other research showing that the biggest bang from the buck is going from the least fit, least active cohort, which we call the bottom 20%, to the next lowest level,” he said in an interview. “So, by simply doing some steps, certainly less than 10,000, there were significant benefits for this older age group.”

Dr. LaCroix acknowledged certain limitations of the OPACH study, including the fact that it did not include men or women aged younger than 60 years. In addition, the accelerometer used in this and other studies may measure fewer steps than women are actually taking. “Devices vary in their accuracy,” she said. “If you are tracking steps, try to aim for 4,500 or a little more, but know that every step counts.”

In a separate study, researchers found that an increase of 30 minutes per day of low-intensity physical activity (LIPA) may lower the risk of death among older adults, regardless of the amount of moderate to vigorous physical activity (MVPA) participants are involved in or whether they have impaired physical function. In addition, an increase of 30 minutes of sedentary time per day may increase the risk of death regardless of the amount of MVPA or whether participants have impaired physical function.

Those are key findings from an analysis of 1,262 participants in the Framingham Offspring Study.

“Given that MVPA tends to decline with age, particularly during the mid- to late-life transition, promoting LIPA and reducing sedentary time may be a more practical alternative among older adults for reducing the risk of mortality,” lead author Joowon Lee, PhD, said in an interview at the meeting sponsored by the American Heart Association.

According to Dr. Lee, a postdoctoral fellow at Boston University, prior studies found that the inverse association between MVPA and cardiovascular and all-cause mortality among older adults. “However, we focused on sedentary and light-intensity physical activity, which is prevalent in older adult population,” he said. “Additionally, we looked at the association between physical activity and mortality after excluding participants with frailty as a sensitivity analysis.”

The researchers drew from accelerometry-derived physical activity data from 1,262 Framingham Offspring Study participants at their ninth examination (2011-2014). The mean age of the subjects was 69 years, 54% were women, and they had worn the accelerometers at least 10 hours per day for at least 4 days prior to the exam visit. The researchers used multivariable Cox proportional hazards regression models to relate physician activity and sedentary time with all-cause mortality adjusting for potential confounders.

During a median follow-up of 4.8 years, 67 study participants died. Dr. Lee and colleagues observed that higher total physical activity, LIPA, adherence to physical activity guidelines (at least 150 minutes of activity each week), and lower sedentary time were associated with a lower risk of all-cause mortality. Specifically, they were 67% less likely to die of any cause if they spent at least 150 minutes per week in moderate to vigorous physical activity, compared with those who did not. In addition, the researchers found that each 30-minute interval of LIPA, such as doing household chores or casual walking, was associated with a 20% lower risk of dying from any cause. On the other hand, every additional 30 minutes of being sedentary was related to a 32% higher risk of dying from any cause. The results remained statistically significant even after excluding those with frailty.

“In the present analysis, an increase of 10 minutes in MVPA was not associated with the risk of all-cause mortality although meeting physical activity guidelines [MVPA of at least 150 minutes per week] was the strongest factor associated with the risk of all-cause mortality,” Dr. Lee said.

He acknowledged certain limitations of the analysis, including the fact that the study participants were white individuals with European ancestry. “Additionally, a small number of mortality events were observed in the current investigation,” he said. “So, an additional study of larger multiethnic samples of older adults is warranted to confirm our findings.”

“We tell people: ‘You need 30 minutes of moderate intensity exercise most days of the week,’ ” Dr. Franklin said. “That’s true, but a classic study in Lancet showed that if you do 12 or 15 minutes of moderate exercise, not 30 minutes, you also get a 14% reduction in mortality. Some exercise is better than none, and for older adults, they don’t even have to do moderate intensity exercise to get benefits.”

Dr. LaCroix’s study was funded by the National Heart, Lung, and Blood Institute; Dr. LaCroix reported having no financial disclosures. Dr. Lee’s study was supported by the National Heart, Lung, and Blood Institute; Dr. Lee reported having no disclosures.

[email protected]

SOURCES: LaCroix A et al. Epi/Lifestyle 2020, Abstract 30; Lee J et al. Epi/Lifestyle 2020, Abstract 31.

PHOENIX – The level of physical activity people engage in during their golden years doesn’t have to be strenuous in order to be effective, results from two studies presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting showed.

Courtesy University of California, San Diego

In one study, women who walked 2,100-4,500 steps each day reduced their risk of dying from cardiovascular disease by up to 38%, compared with those who walked fewer than 2,100 steps each day. In addition, women who walked more than 4,500 steps each day reduced their risk of cardiovascular disease (CVD) mortality risk by 48%.

The findings come from an ancillary analysis of the Women’s Health Study known as the Objective Physical Activity and Cardiovascular Health (OPACH) Study.

“Our work shows that both light-intensity and moderate-/vigorous-intensity steps are associated with reduced risk of cardiovascular disease death,” lead author Andrea Z. LaCroix, PhD, said in an interview. “And our previous studies show that all movement while standing, stepping, or just moving about at whatever intensity you choose, appears to have cardiovascular benefits, whereas long hours spent sedentary, especially prolonged sitting bouts are associated with increased risk of cardiovascular disease. These new findings on steps are best interpreted as showing that moving instead of sitting is good for your heart and blood vessels as we get older. Find the things you love to do and get moving.”

For OPACH, 6,379 women with an average age of 79 years wore ActiGraph GT3X+ triaxial accelerometers on their wrist for 7 days during 2012-2014, as a way to ascertain the number of steps they took. The researchers followed the study participants to March 1, 2019, and used Cox proportional hazard models to estimate CVD mortality across four quartiles of steps per day, adjusted for age, race/ethnicity, education, smoking, alcohol consumption, self-reported health, comorbidities, and physical function. The lowest quartile reference category was less than 2,108 steps per day. The second, third and fourth quartiles were: 2,108 to fewer than 3,136 steps, 3,136 to fewer than 4,499, and 4,500 and above.

Dr. LaCroix, distinguished professor and chief of epidemiology at the University of California, San Diego, reported that women who walked 2,100-4,500 steps daily reduced their risk of dying from CVD by up to up to 38%, compared with women who walked fewer than 2,100 daily steps. The women who walked more than 4,500 steps per day reduced their risk by 48%.

She noted that, for many years, common wisdom was that 10,000 steps per day should be used as a general fitness target, [but] that goal “was never evidence based, and so far, emerging evidence using accelerometers to measure steps shows benefit way below the level of 10,000 steps.” Dr. LaCroix added that, in this study, “we were able separate steps taken at a light intensity of energy expenditure versus a moderate or vigorous level of energy expenditure. This is like comparing slower versus faster steps. Both influenced the risk of CVD death and we found no evidence that faster steps were more beneficial for reducing risk of CVD death than slower steps. So, the main message I want my demographic [women aged over 60] to understand is that all movement appears to be good for your heart.”

Barry A. Franklin, PhD, director of preventive cardiology and cardiac rehabilitation at Beaumont Health in Royal Oak, Mich., characterized the study findings as “good news” but not entirely surprising. “It goes along with other research showing that the biggest bang from the buck is going from the least fit, least active cohort, which we call the bottom 20%, to the next lowest level,” he said in an interview. “So, by simply doing some steps, certainly less than 10,000, there were significant benefits for this older age group.”

Dr. LaCroix acknowledged certain limitations of the OPACH study, including the fact that it did not include men or women aged younger than 60 years. In addition, the accelerometer used in this and other studies may measure fewer steps than women are actually taking. “Devices vary in their accuracy,” she said. “If you are tracking steps, try to aim for 4,500 or a little more, but know that every step counts.”

In a separate study, researchers found that an increase of 30 minutes per day of low-intensity physical activity (LIPA) may lower the risk of death among older adults, regardless of the amount of moderate to vigorous physical activity (MVPA) participants are involved in or whether they have impaired physical function. In addition, an increase of 30 minutes of sedentary time per day may increase the risk of death regardless of the amount of MVPA or whether participants have impaired physical function.

Those are key findings from an analysis of 1,262 participants in the Framingham Offspring Study.

“Given that MVPA tends to decline with age, particularly during the mid- to late-life transition, promoting LIPA and reducing sedentary time may be a more practical alternative among older adults for reducing the risk of mortality,” lead author Joowon Lee, PhD, said in an interview at the meeting sponsored by the American Heart Association.

According to Dr. Lee, a postdoctoral fellow at Boston University, prior studies found that the inverse association between MVPA and cardiovascular and all-cause mortality among older adults. “However, we focused on sedentary and light-intensity physical activity, which is prevalent in older adult population,” he said. “Additionally, we looked at the association between physical activity and mortality after excluding participants with frailty as a sensitivity analysis.”

The researchers drew from accelerometry-derived physical activity data from 1,262 Framingham Offspring Study participants at their ninth examination (2011-2014). The mean age of the subjects was 69 years, 54% were women, and they had worn the accelerometers at least 10 hours per day for at least 4 days prior to the exam visit. The researchers used multivariable Cox proportional hazards regression models to relate physician activity and sedentary time with all-cause mortality adjusting for potential confounders.

During a median follow-up of 4.8 years, 67 study participants died. Dr. Lee and colleagues observed that higher total physical activity, LIPA, adherence to physical activity guidelines (at least 150 minutes of activity each week), and lower sedentary time were associated with a lower risk of all-cause mortality. Specifically, they were 67% less likely to die of any cause if they spent at least 150 minutes per week in moderate to vigorous physical activity, compared with those who did not. In addition, the researchers found that each 30-minute interval of LIPA, such as doing household chores or casual walking, was associated with a 20% lower risk of dying from any cause. On the other hand, every additional 30 minutes of being sedentary was related to a 32% higher risk of dying from any cause. The results remained statistically significant even after excluding those with frailty.

“In the present analysis, an increase of 10 minutes in MVPA was not associated with the risk of all-cause mortality although meeting physical activity guidelines [MVPA of at least 150 minutes per week] was the strongest factor associated with the risk of all-cause mortality,” Dr. Lee said.

He acknowledged certain limitations of the analysis, including the fact that the study participants were white individuals with European ancestry. “Additionally, a small number of mortality events were observed in the current investigation,” he said. “So, an additional study of larger multiethnic samples of older adults is warranted to confirm our findings.”

“We tell people: ‘You need 30 minutes of moderate intensity exercise most days of the week,’ ” Dr. Franklin said. “That’s true, but a classic study in Lancet showed that if you do 12 or 15 minutes of moderate exercise, not 30 minutes, you also get a 14% reduction in mortality. Some exercise is better than none, and for older adults, they don’t even have to do moderate intensity exercise to get benefits.”

Dr. LaCroix’s study was funded by the National Heart, Lung, and Blood Institute; Dr. LaCroix reported having no financial disclosures. Dr. Lee’s study was supported by the National Heart, Lung, and Blood Institute; Dr. Lee reported having no disclosures.

[email protected]

SOURCES: LaCroix A et al. Epi/Lifestyle 2020, Abstract 30; Lee J et al. Epi/Lifestyle 2020, Abstract 31.

PHOENIX – The level of physical activity people engage in during their golden years doesn’t have to be strenuous in order to be effective, results from two studies presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting showed.

Courtesy University of California, San Diego

In one study, women who walked 2,100-4,500 steps each day reduced their risk of dying from cardiovascular disease by up to 38%, compared with those who walked fewer than 2,100 steps each day. In addition, women who walked more than 4,500 steps each day reduced their risk of cardiovascular disease (CVD) mortality risk by 48%.

The findings come from an ancillary analysis of the Women’s Health Study known as the Objective Physical Activity and Cardiovascular Health (OPACH) Study.

“Our work shows that both light-intensity and moderate-/vigorous-intensity steps are associated with reduced risk of cardiovascular disease death,” lead author Andrea Z. LaCroix, PhD, said in an interview. “And our previous studies show that all movement while standing, stepping, or just moving about at whatever intensity you choose, appears to have cardiovascular benefits, whereas long hours spent sedentary, especially prolonged sitting bouts are associated with increased risk of cardiovascular disease. These new findings on steps are best interpreted as showing that moving instead of sitting is good for your heart and blood vessels as we get older. Find the things you love to do and get moving.”

For OPACH, 6,379 women with an average age of 79 years wore ActiGraph GT3X+ triaxial accelerometers on their wrist for 7 days during 2012-2014, as a way to ascertain the number of steps they took. The researchers followed the study participants to March 1, 2019, and used Cox proportional hazard models to estimate CVD mortality across four quartiles of steps per day, adjusted for age, race/ethnicity, education, smoking, alcohol consumption, self-reported health, comorbidities, and physical function. The lowest quartile reference category was less than 2,108 steps per day. The second, third and fourth quartiles were: 2,108 to fewer than 3,136 steps, 3,136 to fewer than 4,499, and 4,500 and above.

Dr. LaCroix, distinguished professor and chief of epidemiology at the University of California, San Diego, reported that women who walked 2,100-4,500 steps daily reduced their risk of dying from CVD by up to up to 38%, compared with women who walked fewer than 2,100 daily steps. The women who walked more than 4,500 steps per day reduced their risk by 48%.

She noted that, for many years, common wisdom was that 10,000 steps per day should be used as a general fitness target, [but] that goal “was never evidence based, and so far, emerging evidence using accelerometers to measure steps shows benefit way below the level of 10,000 steps.” Dr. LaCroix added that, in this study, “we were able separate steps taken at a light intensity of energy expenditure versus a moderate or vigorous level of energy expenditure. This is like comparing slower versus faster steps. Both influenced the risk of CVD death and we found no evidence that faster steps were more beneficial for reducing risk of CVD death than slower steps. So, the main message I want my demographic [women aged over 60] to understand is that all movement appears to be good for your heart.”

Barry A. Franklin, PhD, director of preventive cardiology and cardiac rehabilitation at Beaumont Health in Royal Oak, Mich., characterized the study findings as “good news” but not entirely surprising. “It goes along with other research showing that the biggest bang from the buck is going from the least fit, least active cohort, which we call the bottom 20%, to the next lowest level,” he said in an interview. “So, by simply doing some steps, certainly less than 10,000, there were significant benefits for this older age group.”

Dr. LaCroix acknowledged certain limitations of the OPACH study, including the fact that it did not include men or women aged younger than 60 years. In addition, the accelerometer used in this and other studies may measure fewer steps than women are actually taking. “Devices vary in their accuracy,” she said. “If you are tracking steps, try to aim for 4,500 or a little more, but know that every step counts.”

In a separate study, researchers found that an increase of 30 minutes per day of low-intensity physical activity (LIPA) may lower the risk of death among older adults, regardless of the amount of moderate to vigorous physical activity (MVPA) participants are involved in or whether they have impaired physical function. In addition, an increase of 30 minutes of sedentary time per day may increase the risk of death regardless of the amount of MVPA or whether participants have impaired physical function.

Those are key findings from an analysis of 1,262 participants in the Framingham Offspring Study.

“Given that MVPA tends to decline with age, particularly during the mid- to late-life transition, promoting LIPA and reducing sedentary time may be a more practical alternative among older adults for reducing the risk of mortality,” lead author Joowon Lee, PhD, said in an interview at the meeting sponsored by the American Heart Association.

According to Dr. Lee, a postdoctoral fellow at Boston University, prior studies found that the inverse association between MVPA and cardiovascular and all-cause mortality among older adults. “However, we focused on sedentary and light-intensity physical activity, which is prevalent in older adult population,” he said. “Additionally, we looked at the association between physical activity and mortality after excluding participants with frailty as a sensitivity analysis.”

The researchers drew from accelerometry-derived physical activity data from 1,262 Framingham Offspring Study participants at their ninth examination (2011-2014). The mean age of the subjects was 69 years, 54% were women, and they had worn the accelerometers at least 10 hours per day for at least 4 days prior to the exam visit. The researchers used multivariable Cox proportional hazards regression models to relate physician activity and sedentary time with all-cause mortality adjusting for potential confounders.

During a median follow-up of 4.8 years, 67 study participants died. Dr. Lee and colleagues observed that higher total physical activity, LIPA, adherence to physical activity guidelines (at least 150 minutes of activity each week), and lower sedentary time were associated with a lower risk of all-cause mortality. Specifically, they were 67% less likely to die of any cause if they spent at least 150 minutes per week in moderate to vigorous physical activity, compared with those who did not. In addition, the researchers found that each 30-minute interval of LIPA, such as doing household chores or casual walking, was associated with a 20% lower risk of dying from any cause. On the other hand, every additional 30 minutes of being sedentary was related to a 32% higher risk of dying from any cause. The results remained statistically significant even after excluding those with frailty.

“In the present analysis, an increase of 10 minutes in MVPA was not associated with the risk of all-cause mortality although meeting physical activity guidelines [MVPA of at least 150 minutes per week] was the strongest factor associated with the risk of all-cause mortality,” Dr. Lee said.

He acknowledged certain limitations of the analysis, including the fact that the study participants were white individuals with European ancestry. “Additionally, a small number of mortality events were observed in the current investigation,” he said. “So, an additional study of larger multiethnic samples of older adults is warranted to confirm our findings.”

“We tell people: ‘You need 30 minutes of moderate intensity exercise most days of the week,’ ” Dr. Franklin said. “That’s true, but a classic study in Lancet showed that if you do 12 or 15 minutes of moderate exercise, not 30 minutes, you also get a 14% reduction in mortality. Some exercise is better than none, and for older adults, they don’t even have to do moderate intensity exercise to get benefits.”

Dr. LaCroix’s study was funded by the National Heart, Lung, and Blood Institute; Dr. LaCroix reported having no financial disclosures. Dr. Lee’s study was supported by the National Heart, Lung, and Blood Institute; Dr. Lee reported having no disclosures.

[email protected]

SOURCES: LaCroix A et al. Epi/Lifestyle 2020, Abstract 30; Lee J et al. Epi/Lifestyle 2020, Abstract 31.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

With the novel coronavirus (COVID-19) monopolizing the news cycle, fear and misinformation are at an all-time high. Public health officials and physicians are accelerating education outreach to the public to address misinformation, and identify and care for patients who may have been exposed to the virus.

In times of public health crises, pregnant women have unique and pressing concerns about their personal health and the health of their unborn children. While not often mentioned in major news coverage, obstetricians play a critical role during health crises because of their uniquely personal role with patients during all stages of pregnancy, providing this vulnerable population with the most up-to-date information and following the latest guidelines for recommended care.

Unfortunately, COVID-19 is breaking unfamiliar new ground. We know that pregnant women are at higher risk for viral infection – annually, influenza is a grim reminder that pregnant women are more immunocompromised than the general public – but we do not yet have data to confirm or refute that pregnant women have a higher susceptibility to COVID-19 than the rest of the adult population. We also do not know enough about COVID-19 transmission, including whether the virus can cross the transplacental barrier to affect a fetus, or whether it can be transmitted through breast milk. 

As private practice community obstetricians work to protect their patients during this public health crisis, Ob hospitalists can play an important role in supporting them in the provision of patient care. 

First, Ob hospitalists are highly-trained specialists who can help ensure that pregnant patients who seek care at the hospital – either with viral symptoms or with separate pregnancy-related concerns – are protected during triage until the treating community obstetrician can take the reins.

When a pregnant woman presents at a hospital, in most cases she will bypass the ED and instead be sent directly to the labor and delivery (L&D) unit. During a viral outbreak, there are two major concerns with this approach. For one thing, it means an immunocompromised woman is being sent through the hospital to get to L&D, and along the path, is exposed to every airborne pathogen in the facility (and, if she is already infected, exposes others along the way). In addition, in hospitals without an Ob hospitalist on site, the patient generally is not immediately triaged by a physician, physician’s assistant, or nurse practitioner upon arrival because those clinicians are not consistently on site in L&D.

In times of viral pandemics, new approaches are warranted. For hospitals with contracted L&D management with hospitalists, hospitalists work closely with department heads to implement protocols loosely based on the Emergency Severity Index (ESI) model established by the Agency for Healthcare Research and Quality. Just as the ESI algorithm guides clinical stratification of patients, in times of reported viral outbreaks, L&D should consider triage of all pregnant women at higher levels of acuity, regardless of presentation status. In particular, if they show clinical symptoms, they should be masked, accompanied to the L&D unit by protected personnel, separated from other patients in areas of forced proximity such as hallways and elevators, and triaged in a secure single-patient room with a closed door (ideally at negative pressure relative to the surrounding areas). 

If the patient has traveled to an area of outbreak, reports exposure to travelers who have visited high-risk areas, has had contact with individuals who tested positive for COVID-19, or exhibits any clinical symptoms of COVID-19 (fever, dry cough, fatigue, etc.), her care management should adhere to standing hospital emergency protocols. Following consultation with the assigned community obstetrician, the Ob hospitalist and hospital staff should contact their local/state health departments immediately for all cases of patients who show symptoms to determine if the patient meets requirements for a person under investigation (PUI) for COVID-19. The state/local health department will work with clinicians to collect, store, and ship clinical specimens appropriately. Very ill patients may need to be treated in an intensive care setting where respiratory status can be closely monitored.

At Ob Hospitalist Group, our body of evidence from our large national footprint has informed the development of standard sets of protocols for delivery complications such as preeclampsia and postpartum hemorrhage, as well as a cesarean section reduction toolkit to combat medically unnecessary cesarean sections. OB hospitalists therefore can assist with refining COVID-19 protocols specifically for the L&D setting, using evidence-based data to tailor protocols to address public health emergencies as they evolve.

The second way that Ob hospitalists can support their colleagues is by covering L&D 24/7 so that community obstetricians can focus on other pressing medical needs. From our experience with other outbreaks such as severe acute respiratory syndrome (SARS) and influenza, we anticipate that obstetricians in private practice likely will have their hands full juggling a regular patient load, fielding calls from concerned patients, and caring for infected or ill patients who are being treated in an outpatient setting. Adding to that plate the need to rush to the hospital to clinically assess a patient for COVID-19 or for a delivery only compounds stress and exhaustion. At Ob Hospitalist Group, our hospitalist programs provide coverage and support to community obstetricians until they can arrive at the hospital or when the woman has no assigned obstetrician, reducing the pressure on community obstetricians to rush through their schedules.

Diagnostic and pharmaceutical companies are collaborating with public health officials to expedite diagnostic testing staff, hospital treatment capacity, vaccines, and even early therapies that may help to minimize severity. But right now, as clinicians work to protect their vulnerable patients, a close collaboration between community obstetricians and Ob hospitalists will help to keep patients and health care personnel safe and healthy – a goal that should apply not only to public health crises, but to the provision of maternal care every day.
 

Dr. Simon is chief medical officer at Ob Hospitalist Group (OBHG), is a board-certified ob.gyn., and former head of the department of obstetrics and gynecology for a U.S. hospital. He has no relevant conflicts of interest or financial disclosures. Email him at [email protected].

With the novel coronavirus (COVID-19) monopolizing the news cycle, fear and misinformation are at an all-time high. Public health officials and physicians are accelerating education outreach to the public to address misinformation, and identify and care for patients who may have been exposed to the virus.

In times of public health crises, pregnant women have unique and pressing concerns about their personal health and the health of their unborn children. While not often mentioned in major news coverage, obstetricians play a critical role during health crises because of their uniquely personal role with patients during all stages of pregnancy, providing this vulnerable population with the most up-to-date information and following the latest guidelines for recommended care.

Unfortunately, COVID-19 is breaking unfamiliar new ground. We know that pregnant women are at higher risk for viral infection – annually, influenza is a grim reminder that pregnant women are more immunocompromised than the general public – but we do not yet have data to confirm or refute that pregnant women have a higher susceptibility to COVID-19 than the rest of the adult population. We also do not know enough about COVID-19 transmission, including whether the virus can cross the transplacental barrier to affect a fetus, or whether it can be transmitted through breast milk. 

As private practice community obstetricians work to protect their patients during this public health crisis, Ob hospitalists can play an important role in supporting them in the provision of patient care. 

First, Ob hospitalists are highly-trained specialists who can help ensure that pregnant patients who seek care at the hospital – either with viral symptoms or with separate pregnancy-related concerns – are protected during triage until the treating community obstetrician can take the reins.

When a pregnant woman presents at a hospital, in most cases she will bypass the ED and instead be sent directly to the labor and delivery (L&D) unit. During a viral outbreak, there are two major concerns with this approach. For one thing, it means an immunocompromised woman is being sent through the hospital to get to L&D, and along the path, is exposed to every airborne pathogen in the facility (and, if she is already infected, exposes others along the way). In addition, in hospitals without an Ob hospitalist on site, the patient generally is not immediately triaged by a physician, physician’s assistant, or nurse practitioner upon arrival because those clinicians are not consistently on site in L&D.

In times of viral pandemics, new approaches are warranted. For hospitals with contracted L&D management with hospitalists, hospitalists work closely with department heads to implement protocols loosely based on the Emergency Severity Index (ESI) model established by the Agency for Healthcare Research and Quality. Just as the ESI algorithm guides clinical stratification of patients, in times of reported viral outbreaks, L&D should consider triage of all pregnant women at higher levels of acuity, regardless of presentation status. In particular, if they show clinical symptoms, they should be masked, accompanied to the L&D unit by protected personnel, separated from other patients in areas of forced proximity such as hallways and elevators, and triaged in a secure single-patient room with a closed door (ideally at negative pressure relative to the surrounding areas). 

If the patient has traveled to an area of outbreak, reports exposure to travelers who have visited high-risk areas, has had contact with individuals who tested positive for COVID-19, or exhibits any clinical symptoms of COVID-19 (fever, dry cough, fatigue, etc.), her care management should adhere to standing hospital emergency protocols. Following consultation with the assigned community obstetrician, the Ob hospitalist and hospital staff should contact their local/state health departments immediately for all cases of patients who show symptoms to determine if the patient meets requirements for a person under investigation (PUI) for COVID-19. The state/local health department will work with clinicians to collect, store, and ship clinical specimens appropriately. Very ill patients may need to be treated in an intensive care setting where respiratory status can be closely monitored.

At Ob Hospitalist Group, our body of evidence from our large national footprint has informed the development of standard sets of protocols for delivery complications such as preeclampsia and postpartum hemorrhage, as well as a cesarean section reduction toolkit to combat medically unnecessary cesarean sections. OB hospitalists therefore can assist with refining COVID-19 protocols specifically for the L&D setting, using evidence-based data to tailor protocols to address public health emergencies as they evolve.

The second way that Ob hospitalists can support their colleagues is by covering L&D 24/7 so that community obstetricians can focus on other pressing medical needs. From our experience with other outbreaks such as severe acute respiratory syndrome (SARS) and influenza, we anticipate that obstetricians in private practice likely will have their hands full juggling a regular patient load, fielding calls from concerned patients, and caring for infected or ill patients who are being treated in an outpatient setting. Adding to that plate the need to rush to the hospital to clinically assess a patient for COVID-19 or for a delivery only compounds stress and exhaustion. At Ob Hospitalist Group, our hospitalist programs provide coverage and support to community obstetricians until they can arrive at the hospital or when the woman has no assigned obstetrician, reducing the pressure on community obstetricians to rush through their schedules.

Diagnostic and pharmaceutical companies are collaborating with public health officials to expedite diagnostic testing staff, hospital treatment capacity, vaccines, and even early therapies that may help to minimize severity. But right now, as clinicians work to protect their vulnerable patients, a close collaboration between community obstetricians and Ob hospitalists will help to keep patients and health care personnel safe and healthy – a goal that should apply not only to public health crises, but to the provision of maternal care every day.
 

Dr. Simon is chief medical officer at Ob Hospitalist Group (OBHG), is a board-certified ob.gyn., and former head of the department of obstetrics and gynecology for a U.S. hospital. He has no relevant conflicts of interest or financial disclosures. Email him at [email protected].

With the novel coronavirus (COVID-19) monopolizing the news cycle, fear and misinformation are at an all-time high. Public health officials and physicians are accelerating education outreach to the public to address misinformation, and identify and care for patients who may have been exposed to the virus.

In times of public health crises, pregnant women have unique and pressing concerns about their personal health and the health of their unborn children. While not often mentioned in major news coverage, obstetricians play a critical role during health crises because of their uniquely personal role with patients during all stages of pregnancy, providing this vulnerable population with the most up-to-date information and following the latest guidelines for recommended care.

Unfortunately, COVID-19 is breaking unfamiliar new ground. We know that pregnant women are at higher risk for viral infection – annually, influenza is a grim reminder that pregnant women are more immunocompromised than the general public – but we do not yet have data to confirm or refute that pregnant women have a higher susceptibility to COVID-19 than the rest of the adult population. We also do not know enough about COVID-19 transmission, including whether the virus can cross the transplacental barrier to affect a fetus, or whether it can be transmitted through breast milk. 

As private practice community obstetricians work to protect their patients during this public health crisis, Ob hospitalists can play an important role in supporting them in the provision of patient care. 

First, Ob hospitalists are highly-trained specialists who can help ensure that pregnant patients who seek care at the hospital – either with viral symptoms or with separate pregnancy-related concerns – are protected during triage until the treating community obstetrician can take the reins.

When a pregnant woman presents at a hospital, in most cases she will bypass the ED and instead be sent directly to the labor and delivery (L&D) unit. During a viral outbreak, there are two major concerns with this approach. For one thing, it means an immunocompromised woman is being sent through the hospital to get to L&D, and along the path, is exposed to every airborne pathogen in the facility (and, if she is already infected, exposes others along the way). In addition, in hospitals without an Ob hospitalist on site, the patient generally is not immediately triaged by a physician, physician’s assistant, or nurse practitioner upon arrival because those clinicians are not consistently on site in L&D.

In times of viral pandemics, new approaches are warranted. For hospitals with contracted L&D management with hospitalists, hospitalists work closely with department heads to implement protocols loosely based on the Emergency Severity Index (ESI) model established by the Agency for Healthcare Research and Quality. Just as the ESI algorithm guides clinical stratification of patients, in times of reported viral outbreaks, L&D should consider triage of all pregnant women at higher levels of acuity, regardless of presentation status. In particular, if they show clinical symptoms, they should be masked, accompanied to the L&D unit by protected personnel, separated from other patients in areas of forced proximity such as hallways and elevators, and triaged in a secure single-patient room with a closed door (ideally at negative pressure relative to the surrounding areas). 

If the patient has traveled to an area of outbreak, reports exposure to travelers who have visited high-risk areas, has had contact with individuals who tested positive for COVID-19, or exhibits any clinical symptoms of COVID-19 (fever, dry cough, fatigue, etc.), her care management should adhere to standing hospital emergency protocols. Following consultation with the assigned community obstetrician, the Ob hospitalist and hospital staff should contact their local/state health departments immediately for all cases of patients who show symptoms to determine if the patient meets requirements for a person under investigation (PUI) for COVID-19. The state/local health department will work with clinicians to collect, store, and ship clinical specimens appropriately. Very ill patients may need to be treated in an intensive care setting where respiratory status can be closely monitored.

At Ob Hospitalist Group, our body of evidence from our large national footprint has informed the development of standard sets of protocols for delivery complications such as preeclampsia and postpartum hemorrhage, as well as a cesarean section reduction toolkit to combat medically unnecessary cesarean sections. OB hospitalists therefore can assist with refining COVID-19 protocols specifically for the L&D setting, using evidence-based data to tailor protocols to address public health emergencies as they evolve.

The second way that Ob hospitalists can support their colleagues is by covering L&D 24/7 so that community obstetricians can focus on other pressing medical needs. From our experience with other outbreaks such as severe acute respiratory syndrome (SARS) and influenza, we anticipate that obstetricians in private practice likely will have their hands full juggling a regular patient load, fielding calls from concerned patients, and caring for infected or ill patients who are being treated in an outpatient setting. Adding to that plate the need to rush to the hospital to clinically assess a patient for COVID-19 or for a delivery only compounds stress and exhaustion. At Ob Hospitalist Group, our hospitalist programs provide coverage and support to community obstetricians until they can arrive at the hospital or when the woman has no assigned obstetrician, reducing the pressure on community obstetricians to rush through their schedules.

Diagnostic and pharmaceutical companies are collaborating with public health officials to expedite diagnostic testing staff, hospital treatment capacity, vaccines, and even early therapies that may help to minimize severity. But right now, as clinicians work to protect their vulnerable patients, a close collaboration between community obstetricians and Ob hospitalists will help to keep patients and health care personnel safe and healthy – a goal that should apply not only to public health crises, but to the provision of maternal care every day.
 

Dr. Simon is chief medical officer at Ob Hospitalist Group (OBHG), is a board-certified ob.gyn., and former head of the department of obstetrics and gynecology for a U.S. hospital. He has no relevant conflicts of interest or financial disclosures. Email him at [email protected].

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

copyright/Thinkstock

The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

copyright/Thinkstock

The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

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The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.